Cu(i)-catalyzed azide-alkyne cycloadditions (CUAAC) ligands and methods for carrying out cu(i)-catalyzed azide-alkyne cycloaddition reactions

Abstract

A Cu(I)-Catalyzed Azide-Alkyne Cycloadditions (CuAAC) ligand comprising: a catalytic core; a fluorous tag; and a linker binding the fluorous tag to the catalytic core. A method for carrying out a Cu(I)-Catalyzed Azide-Alkyne Cycloaddition reaction, comprising: combining in a solution an alkyne-tagged component, an azide-tagged component and a Cu(I)-Catalyzed Azide-Alkyne Cycloadditions (CuAAC) ligand comprising: a catalytic core; a fluorous tag; and a linker binding the fluorous tag to the catalytic core; filtering the solution through a solid phase extraction filter to remove Cu(I)-ligand catalyst and / or excess ligand.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of the filing date of U.S. provisional patent application Ser. No. 62 / 057,986, filed on Sep. 30, 2014, the entirety of which is incorporated herein by reference for all purposes.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under NIH grant #EB017317. The government has certain rights in the invention.BACKGROUND OF THE DISCLOSURE[0003]Click chemistry, particularly the copper(I)-catalyzed azide alkyne cycloaddition (CuAAC), has found applications in a wide range of modern chemistry-related areas, including organic chemistry, drug discovery, drug delivery and chemical biology. However, the toxicity of copper(I) from the generation of reactive nitrogen and oxygen species limits its application in living systems. For example, upon treatment of 1 mM CuSO4, 1.5 mM sodium ascorbate, and 0.1 mM TBTA, Zebrafish embryos do not survive beyond 15...

AI Technical Summary

Benefits of technology

The present disclosure provides a new series of copper(I)-stabilizing ligands that combine the benefits of fluorous separation tags and bis(tert-butyltriazoly)amine catalyst cores. These ligands enable rapid and efficient copper(I)-catalyzed azide-alkyne cycloaddition reactions, resulting in the production of high purity radiotracers without toxicity. The fluorous tag allows for easy removal of the toxic catalyst from the product, while the linker between the fluorous tag and catalytic core provides necessary distance to reduce steric effects and improve aqueous solubility. The preferred ligands have significantly higher efficiency and solubility compared to commercial ligands, and can be used for the synthesis of various radiopharmaceuticals.

Problems solved by technology

However, the toxicity of copper(I) from the generation of reactive nitrogen and oxygen species limits its application in living systems.

Therefore, the removal of copper species is typically required in order to avoid cytotoxicity caused by residual copper ions in biological applications, adding another layer of complexity to the application of CuAAC in living systems.

However, these strategies cannot fulfill all the requirements due to their inherent deficiencies, including relatively sluggish kinetics in SPAAC and copper leaching problems observed in the resin-supported catalyst systems.

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